Non-constant pressure infusion pump

ABSTRACT

The present invention relates to an implantable infusion pump having a refillable infusate reservoir in fluid communication with a delivery site via a flow path. This flow path includes a flow resistance. The infusion pump includes a sensing device(s), positioned relative to the flow path, to provide data regarding a flow rate along the flow path. The infusion pump effects a division of a total flow period into at least a plurality of unit dose periods, each unit dose period effecting delivery of a unit dose of infusate. The cumulative effect of delivering the total number of unit dose periods is the delivery of a desired dose over the total flow period. The present invention permits a reservoir pressure to vary over any portion of total flow period but effects a constant-pressure state over each unit dose cycle.

FIELD OF THE INVENTION

[0001] The present invention relates to an implantable infusion pump,and in particular, to an infusion pump capable of effecting a preciselycontrolled (constant or variable) fluid flow delivery rate, independentof a constant reservoir pressure.

BACKGROUND OF THE INVENTION

[0002] Modern implantable infusion devices, or implantable pumps, fordelivering an infusate (e.g., medicaments, insulin, etc.) commonly havea rigid housing that maintains a collapsible infusate reservoir. Thehousing includes a needle-penetrable septum that covers a reservoirinlet. A flow passage is provided between the reservoir and an exteriorsurface of the device. At the flow passage outlet, a flexible deliverycatheter is provided.

[0003] These devices are implanted at a selected location in a patient'sbody so that (i) the inlet septum is proximate to the patient's skin and(ii) a distal end of the catheter is positioned at a selected deliverysite. Infusate can then be delivered to the infusion site by controllingthe flow of such fluid from the device infusate reservoir into thedelivery catheter. When the infusate reservoir becomes empty, thereservoir is refillable through the reservoir inlet by injecting a newsupply of infusate through the apparatus' inlet septum. Due to thelocation of the device in relation to the skin of the patient, injectioncan be readily accomplished using a hypodermic needle (or cannula).

[0004] Infusate is expelled from the reservoir to an infusion site bycollapsing the reservoir. Some infusion pumps use an electricallypowered mechanism to “actively” pump infusate from the infusatereservoir into the delivery catheter. Examples of these types of“factive pumping” devices include so-called peristaltic pumps (e.g.,SynchroMed® implantable pump from Medtronic, Inc., Minneapolis, Minn.)and accumulator-type pumps (e.g., certain external infusion pumps fromMinimed, Inc., Northridge, Calif. and Infusaid® implantable pump fromStrato/Infusaid, Inc., Norwood, Mass.). These devices have certainadvantages; however, such devices have a large disadvantage in that theyuse relatively large amounts of battery power to effect infusion. Giventhat batteries tend to add bulk and weight and their replacementrequires surgical intervention, it is very desirable to minimize powerconsumption in implantable infusion pumps.

[0005] Another type of implantable pump that is typically much moreelectrically efficient uses a passive pumping mechanism. In fact,certain of these devices can be constructed and operated without anyelectrical power at all. A passive pumping mechanism generally consistsof a means of pressurizing the infusate reservoir and a means ofrestricting the fluid flow. All of these devices operate under theprinciple that the fluid flow rate (Q) is directly proportional to apressure difference (ΔP) between the infusate reservoir interior and thedelivery site and inversely proportional to the total flow resistanceprovided by the fluid passage and delivery catheter (collectively (R)),wherein

Q=ΔP÷R

[0006] A practical pump must have a predictable flow rate (Q). Toachieve this goal, conventional designs have strived to developsubstantially constant pressure sources.

[0007] The first means of developing such a “constant pressure source”includes using a two-phase fluid, or propellant, that is containedwithin the rigid housing and is further confined within a fluid-tightspace adjacent to the infusate reservoir. Pumps constructed in thismanner are called “gas-driven” pumps.

[0008] The propellant is both a liquid and a vapor at patientphysiological temperatures, e.g., 98.6° F., and theoretically exerts apositive, constant pressure over a full volume change of the reservoir,thus effecting the delivery of a constant flow of infusate. When theinfusate reservoir is expanded upon being refilled, a portion of suchvapor reverts to its liquid phase and thereby maintains a state ofequilibrium between the fluid and gas states at a “vapor pressure,”which is a characteristic of the propellant. The construction andoperation of implantable infusion pumps of this type are described indetail, for example, in U.S. Pat. Nos. 3,731,681 and 3,951,147. Pumps ofthis type are commercially available, for example, Model 3000™from ArrowInternational, Reading, Penn. and IsoMed® from Medtronic, Inc.,Minneapolis, Minn.

[0009] Gas-driven infusion pumps typically provide an electricallyefficient means to deliver a flow of infusate throughout a deliverycycle. However, such infusion pumps depend upon a constant pressuresource, wherein the output fluid flow rate is directly proportional to apropellant-reservoir pressure. If the propellant-reservoir pressurevaries, then so will the fluid flow rate and the drug delivery rate.

[0010] The propellant-reservoir pressure of conventional gas-driveninfusion pumps are susceptible to changes in ambient temperature andpressure. This, in turn, makes the fluid flow rate such devicessusceptible to changes in ambient temperature and pressure. Such changesin drug infusion rates are undesirable and, in certain situations,unacceptable.

[0011] Circumstances readily exist where either ambient temperature orpressure can rapidly change a significant amount. For example, thereservoir pressure of some conventional gas-driven pumps can change asmuch as 0.5 psi for each 1° F. change in body temperature. Thus, forexample, assuming a pump driving force of 8 psi at 98.6° F., a fever ofonly 102.6° F. can result in a twenty-five percent (25%) increase inpropellant-reservoir pressure and thus, a corresponding (or larger)increase in an fluid flow rate. In addition, changes in environmentaltemperature affect the infusate viscosity as well as the vapor pressureproduced by the propellant, thereby further increasing the pump'ssusceptibility to temperature.

[0012] An even more serious situation results from changes in ambientpressure. Although minor variations in ambient pressure at any givenlocation on earth may not significantly affect delivery flow rates, withmodern modes of transportation, a patient can rapidly change altitudeduring travel, such as when traveling in the mountains or when travelingby plane. In a like manner, a patient can experience a rapid change inpressure when swimming or diving.

[0013] The rigid housing of the conventional, gas-driven infusion pumpprovides an absolute constant-internal pressure (P_(R)) (at constanttemperature) independent of external pressures. However, largely due tocompliance by the lungs and venous circulatory system, hydrostaticpressure within the human body closely follows ambient pressure (P_(D)).

[0014] The net effect is that the pressure differential (ΔP=P_(R)−P_(D))in conventional gas-driven pumps changes linearly with ambient pressure.Consequently, a delivered infusate flow rate can increase as much asforty percent (40%) when a patient takes a common commercial airlineflight.

[0015] To overcome these practical circumstances, some conventionalgas-driven infusion devices have been provided with elevated reservoirpressures. The increased reservoir pressures are not intended to preventvariations in a constant pressure delivery but are intended to mitigatetheir effect. In particular, for any given change of pressure, theeffect on flow rate is effectively lessened if the total percentage ofpressure change (relative to the reservoir pressure) can be reduced.These infusion devices possess undesirable attributes in that refillingoperations are more difficult and the high-pressure vessels, which formthe pump housing structures, must necessarily be stronger and aretherefore more susceptible to manufacturing problems.

[0016] Another method of attempting to produce a constant pressuresource and thereby more accurately controlling a rate of fluid deliveryis to incorporate a pressure regulator, such as that disclosed in U.S.Pat. No. 4,299,220. The pressure regulator described therein, which ispositioned between the infusate reservoir and delivery catheter, uses adiaphragm valve to maintain a constant pressure differential (ΔP) acrossthe fluid flow restrictor. In addition to increasing the operationalcomplexity of such a pump mechanism and the volume of a fluid pathextending therethrough, the pressure regulator may, depending upondevice configuration, subject infusate solutions to high local shearstresses, which may alter the chemical or therapeutic properties ofcertain infusates.

[0017] An alternative method for attempting to produce a constantpressure source and thereby more accurately controlling a rate of fluiddelivery, as well as addressing the susceptibilities of the two-phasepumps to ambient temperature and pressure, is proposed in U.S. Pat. No.4,772,263. Specifically, in place of the conventional rigid enclosurethat maintains a two-phase fluid, the disclosure teaches forming thefluid reservoir between a rigid portion (which maintains at least theinlet septum) and a flexible drive-spring diaphragm. The springdiaphragm is exposed to the body of the patient and the pressuretherein. The spring diaphragm creates a more desirable “relative” (asopposed to an absolute) pressure source. By exposing the springdiaphragm to the pressures inside the body it is possible for the pumpto respond and react to changes in ambient pressure so that ΔP isunaffected. Likewise, it is possible to construct the spring diaphragmso that the pressure that it generates is not affected by changes inambient temperature. While this configuration offers practicalperformance advantages, this design offers a unique configuration thatmay not be adopted by all constant flow pump designs.

[0018] Accordingly, a need exists for an electrically efficient systemto enable a controllable (constant or variable) fluid flow delivery rateindependent of either a constant reservoir pressure or externalconditions that may otherwise result in undesirable or unpredictableoutput fluid flow variations.

SUMMARY OF THE INVENTION

[0019] An object of the present invention is to provide an implantableinfusion device with a non-constant reservoir pressure (over at least aportion of the flow cycle) that controls fluid flow across a fluid flowrestrictor (with or without other fluid control elements) by dividing agreater dose cycle into a series of (smaller) unit dose cycles overwhich the reservoir pressure is substantially constant.

[0020] Another object of the present invention is to provide anelectrically efficient implantable infusion device, having a convenientpressure reservoir, that is capable of delivering a prescribed dosage ofa fluid infusate independent of either a constant reservoir pressure,ambient temperature or pressure, changes in device performance, orinfusate properties.

[0021] Another objective of the present invention is to provide animplantable infusion device that is simpler in construction.

[0022] The present invention is directed to a controlled-rate infusiondevice for implantation in a living body. The infusion device includes acollapsible infusate chamber, an energy source to collapse the chamber,and an outlet flow path extending between the chamber and a deviceoutlet. The infusion device further includes at least one flowrestrictor, a controller, at least one valve or variable flow restrictorto selectively alter a flow resistance of the outlet flow path, and atleast one pressure sensing device. The pressure sensing device(s) arepositioned relative to the outlet flow path as well as about the flowresistance (i.e., any combination of flow restrictors and/or valves).The controller is adapted to control an operation of the valve (orvariable flow restrictor) based on measured value(s) obtained by thepressure sensing device(s).

[0023] In another aspect, the present invention is directed to acontrolled-rate infusion device for implantation in a living body. Theinfusion device includes a collapsible infusate chamber, an energysource to collapse the chamber, and an outlet flow path extendingbetween the chamber and a device outlet. The infusion device furtherincludes a controller, a valve (or variable flow restrictor) toselectively obstruct the outlet flow path, and one or more pressuresensing devices. The pressure sensing devices are positioned relative tothe outlet flow path as well as about the flow resistance. Thecontroller is adapted to assess whether output flow from the device isundesirably restricted based on measured values obtained from thepressure sensing devices.

[0024] Another aspect of the present invention is directed to a methodfor controlling infusate output from an implantable-infusion device fora prescribed dose period. The device includes a collapsible infusatechamber, an energy source to collapse the chamber, and an outlet flowpath extending between the chamber and a device outlet, and the outletflow path includes a restrictor network, which includes an occlusiondevice to selectively and at least partially occlude the outlet flowpath. The method includes the steps of: (i) dividing the prescribed doseperiod into a plurality of unit dose periods, wherein each unit doseperiod is defined by an open-close cycle of the valve; and (ii)modifying a duty cycle of the open-close cycle of the valve so as tomaintain a prescribed output volume (i.e., a unit dose) for each unitdose period.

[0025] Another aspect of the method for controlling infusate output froman implantable infusion device can include, independent of or incooperation with other aspects of this method, measuring an infusatepressure differential across the restrictor network (or a portionthereof). Thus, the step of modifying the duty cycle is performed inaccordance with a measured infusate pressure differential.

[0026] Another aspect of the method for controlling infusate output froman implantable infusion device can include, independent of or incooperation with other aspects of this method, actuating the valve so asto effect a change in an occluded state of the outlet flow path. Duringor proximate to such actuation, a transient pressure profile on one sideof the valve is measured, thus enabling an assessment of the performanceof the valve, fluid path, flow restrictor and any other elements of theflow control system or flow path.

[0027] Another aspect of the method for controlling infusate output froman implantable infusion device can include, independent of or incooperation with other aspects of this method, measuring an infusatetemperature. Thus, the step of modifying the duty cycle is performed inaccordance with a measured infusate temperature.

[0028] Another aspect of the present invention is that an output flowrate of a controlled rate pump can be changed by “resetting,” orprogramming, such output flow rate. This resetting operation can beaccomplished using non-invasive (e.g., magnetic switch, radio-frequencytelemetry) or invasive methods (e.g., transcutaneous trocar). In thisway, the methods and devices described herein can be used to construct aprogrammable pump, the flow rate of which can be manually orautomatically (responsive to a clock, sensor, or other data input)modified to any of various beneficial patterns.

[0029] Other objects and advantages of the present invention will beapparent to those of ordinary skill in the art having reference to thefollowing specification together with the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In the drawings, like reference numerals and letters indicatecorresponding parts throughout the several illustrations:

[0031]FIG. 1 schematically illustrates a conventional implantableinfusion device for delivering an infusate at a prescribed rateincorporating a passive pumping mechanism;

[0032]FIG. 2A schematically illustrates an implantable infusion devicein accordance with one embodiment of the present invention, FIG. 2Bschematically illustrates an implantable infusion device in accordancewith another embodiment of the present invention, and FIG. 2Cschematically illustrates an implantable infusion device in accordancewith another embodiment of the present invention;

[0033]FIG. 3 illustrates an exemplary timing chart corresponding tovalve control for regulating a delivery of infusate from an infusatereservoir of the implantable infusion device of either FIG. 2A, 2B, orFIG. 2C;

[0034]FIG. 4 schematically illustrates an implantable infusion device inaccordance with another embodiment of the present invention;

[0035]FIG. 5 partially illustrates a schematic representation of animplantable infusion device in accordance with another embodiment of thepresent invention;

[0036]FIG. 6 partially illustrates a schematic representation of animplantable infusion device in accordance with another embodiment of thepresent invention;

[0037]FIG. 7 partially illustrates a schematic representation of animplantable infusion device in accordance with another embodiment of thepresent invention;

[0038]FIG. 8 partially illustrates a schematic representation of animplantable infusion device in accordance with another embodiment of thepresent invention;

[0039]FIG. 9 partially illustrates a schematic representation of animplantable infusion device in accordance with another embodiment of thepresent invention;

[0040]FIG. 10 partially illustrates a schematic representation of animplantable infusion device in accordance with another embodiment of thepresent invention; and

[0041]FIG. 11 partially illustrates a schematic representation of animplantable infusion device in accordance with another embodiment of thepresent invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Various embodiments, including preferred embodiments, will now bedescribed in detail below with reference to the drawings.

[0043]FIG. 1 illustrates a conventional, constant flow rate infusiondevice 10. The device 10 is characterized by an infusate reservoir 12that is required to store a prescribed volume of infusate, e.g.,insulin, medicament, pain relieving drugs, etc. The infusate reservoir12 is of sufficient volume so as to provide a supply of infusate (i.e.,a prescribed dose (D)) over a flow period (τ) at a (theoretically)constant flow rate. As but one possible example, the volume of theinfusate reservoir 12 can be fixed at any prescribed volume to enabledelivery of a precisely controlled volume of infusate from one day tomore than three months. The infusate reservoir 12 can be refilledthrough a septum 14.

[0044] Infusate is pressurized and thereby driven from the infusatereservoir 12 by a drive source 16. The physical nature of the drivesource 16 can be a two-phase fluid, which is confined between thehousing of the device 10 and a movable diaphragm structure 18, a drivespring that forms the diaphragm structure 18, or likemechanisms/structures that develop a substantially constant pressure. Aflow restrictor 20 is positioned downstream from the infusate reservoir12 to establish an output flow rate. The flow restrictor 20 can beconstructed of any number of potential structures, for example, a platehaving a groove formed therein, capillary tubing, an etched flow chip,or the like. Although not shown, a filter is preferably interpositionedbetween the infusate reservoir 12 and the restrictor 20 to prevent anybacteria present in the infusate reservoir 12 from being transferredinto the body, and to a certain extent, to protect the restricted flowpath defined by the restrictor 20. Flow from the flow restrictor 20 ispassed to a catheter 22 having its distal end positioned at a site forfluid delivery.

[0045] Conventional implantable infusion devices can further include abolus port structure 24. The bolus port structure 24, whether integralwith the device 10 or separate therefrom, provides direct fluidcommunication with the catheter 22. The bolus port structure 24 isadapted to receive independently a hypodermic needle (or cannula). Fluiddelivered to the bolus port structure 24 can be used to flush thedownstream catheter 22, deliver a prescribed dosage of medicament(possibly of a volume greater or at a rate greater than that otherwisecapable to be delivered through the flow restrictor 20), or performtroubleshooting or diagnostic procedures. Depending on the configurationof the bolus port structure 24, the structure 24 can also allowextraction of fluid from the patient via the catheter 22.

[0046]FIG. 2A illustrates one embodiment of the present invention.Specifically, an implantable infusion device has a infusate reservoir 12connected between a septum 14 and a flow restrictor 20. Infusate withinthe infusate reservoir 12 is pressurized and thereby driven through theflow restrictor 20 by the drive source 16. The illustrated infusiondevice includes a first pressure sensing device 24, to measure apressure upstream of the flow restrictor 20, and a second pressuresensing device 26, to measure a pressure downstream of the flowrestrictor 20. Respective positions of the pressure sensing devices 24and 26 relative to a flow path through the infusion device are notcritical so long as the pressure sensing device 24 remains upstream ofthe flow restrictor 20 and the pressure sensing device 26 remainsdownstream of the flow restrictor 20. Alternatively, given that the flowrate will be determined by a pressure differential (ΔP) at the point ofthe pressure sensing devices 24 and 26, it is also possible to measurethis pressure differential (ΔP) with a single pressure transducer,operatively coupled to the flow path at or about the same two points asotherwise occupied by the pressure sensing devices 24 and 26 (FIG. 2A orFIG. 4) or as otherwise occupied by the pressure sensing devices 24 and40 (FIG. 4), as illustrated in FIGS. 2B and 2C.

[0047] It will be readily apparent to those of ordinary skill in the artthat a multitude of configurations are within the scope of the presentinvention, such configurations including at least one flow restrictor,one pressure sensor, and a mechanism to change the total flow resistanceof the system. To this end, FIGS. 2A to 11 illustrate some of thepossible configuration-combinations that includes: (i) one or more flowrestrictors arranged in parallel, series, or combinations thereof; (ii)one or more valves, whereby these elements can affect an overall flowresistance; and (iii) one or more pressure sensors that are capable ofdetermining a pressure difference across any portion of or all of theflow restrictors or valves. In regard to (ii) above, depending upon theintended use of the infusion device, it may be desirable to use fixed orvariable flow restrictors, which includes mono-stable, bi-stable, ormulti-stable valves that have the potential of occluding or partiallyoccluding the possible flow paths.

[0048] A valve 28 is positioned downstream of the flow restrictor 20,and is preferably positioned downstream of the pressure sensing device26. Accordingly, the pressure sensing device 24 can be positioned withinor proximate to the infusate reservoir 12, and the pressure sensingdevice 26 can be positioned subsequent to the valve 28.

[0049] A controller 30 (e.g., a microprocessor) is electricallyconnected to the pressure sensing device 24, the pressure sensing device26, and the valve 28. The controller 30 functions to control fluid flowthrough the valve 28 based on respective outputs from pressure sensingdevices 24 and 26.

[0050] A fluid flow rate across the flow restrictor 20 can be calculatedfrom:

Q=(P _(R) −P _(D))÷R

[0051] where,

[0052] Q is a flow rate output from the catheter 22;

[0053] P_(R) is a measured reservoir pressure;

[0054] P_(D) is a measured delivery pressure; and

[0055] R is a flow resistance value of the flow path as a whole, whichcan be approximated by the resistive value of the flow restrictor 20(when the valve is in an open state).

[0056] An optional temperature sensing device 38 can also be coupled tothe controller 30. If provided, the controller 30 would function tocontrol fluid flow through the valve 28 also in consideration of (orsolely based on) an output from the temperature sensing device 38. Thecontroller 30 is adapted to relate changes in an infusate temperature toproportional changes in system pressure and/or to changes in theresistive value (R), the latter being caused by a change in fluidviscosity due to a change in infusate temperature. This ability of thecontroller 30 is managed by algorithms or look-up tables stored inmemories 32 and/or 34.

[0057] A flow cycle of an infusion device is considered to extendthrough the delivery of the contents of the infusate reservoir 12, i.e.,from a refilling event until a subsequent refilling event. The quantity(S) of active pharmacological agents or other agents (individually orcollectively “agent”) contained in the infusate reservoir 12 dependsupon the fluid volume (V) of the infusate reservoir 12 and theconcentration of the agent in the infusate stored therein:

S=V*C

[0058] where,

[0059] S is the quantity (e.g., mg) of the agent,

[0060] C is the agent concentration in the infusate contained in theinfusate reservoir 12, and

[0061] V is the fluid volume of the infusate reservoir 12.

[0062] The duration of the flow cycle is referred to as the flow period(τ). As is probable, the flow period will typically be between 1 andover three (3) months. It is related to the flow rate (Q) and theinfusate reservoir volume (V) as follows:

τ=V÷Q

[0063] where,

[0064] τ is the flow period (e.g., days), and

[0065] Q is the infusate flow rate (e.g., ml/day).

[0066] A prescribed (or desired) dose (D) delivered must be furthercalculated in accordance with the following:

D=Q*C

[0067] where,

[0068] D is the quantity of an agent delivered per unit of time (e.g.,mg/day).

[0069] As discussed above, conventional constant flow infusion devicesdeliver a single prescribed dose (D) based on the assumption that aconstant pressure is maintained over an entire flow period (τ). As alsodiscussed above, this assumption can be realistically compromised bychanges in ambient pressure or temperature, patient position, orinfusate volume residing in the reservoir throughout a flow period (τ).Moreover, the total flow resistance (R) provided by the flow path canchange over the lifetime of the infusion device further affecting thedischarge performance of the device. Moreover, the properties of theinfusate can change over the lifetime of the infusion device, furtheraffecting the therapy.

[0070] In contrast, the devices of the present invention seek to providethe desired flow accuracy in spite of the fact that the pressuredifferential (ΔP) and/or flow resistance (R) may not remain constantover the entire flow period (τ). These devices do this by subdividingthe flow period (τ) into smaller unit dose periods (t_(i,j)) over whichthe flow parameters (ΔP) and (R) are likely to remain constant anddelivering the total dose (D) though a series of sequential unit doseperiods (t_(i,j)). The following definitions and equations help tounderstand the present invention.

[0071] A flow period (τ) can be subdivided into any number (n) ofprescribed dose periods (T_(i)), which may or may not be of equalduration. For conventional constant flow pumps, n=1. For the presentinvention, “n” may be any integer, preferably two or greater.$\tau = {\sum\limits_{i = 1}^{n}T_{i}}$

[0072] For various embodiments of the present invention, the duration ofthe prescribed dose periods (T_(i)) may or may not bephysician-alterable (i.e., to create a programmable pump) and/orpatient-alterable (i.e., to create a programmable pump withpatient-controllable elements) either before or during the flow period(Δ).

[0073] During each of the prescribed dose periods (T_(i)) a prescribeddose (D_(i)) is delivered. If all of these prescribed doses (D_(i)) areequal, then the equations describe a constant flow infusion device,possibly with improved flow accuracy such as, for example, illustratedin FIG. 2A. If there are multiple prescribed doses (D_(i)) of differentmagnitudes, then the equations describe a programmable pump operatingwith a complex continuous infusion pattern. The therapeutic value ofthese complex infusion patterns is readily apparent to clinicians, andvaries depending upon the agent, patient, and application.

[0074] In all applications, a certain quantity of drug (s_(i)) is to bedelivered in the dose period (T_(i)) at a prescribed dose (D_(i)). Thefollowing equations illustrate the relationship among these variables,$S = {{\sum\limits_{i = 1}^{n}s_{i}} = {\sum\limits_{i = 1}^{n}{D_{i}*T_{i}}}}$

[0075] In the present invention, each of the prescribed dose periods(T_(i)) is further divided into any number (m_(i)) of unit dose periods(t_(i,j)). For the present invention, “m” may be any integer, one orgreater. In a preferred embodiment, all of the unit dose periods(t_(i,j)) within a given prescribed dose period (T₁) are equal. Thissimplifies the calculations necessary for device operation; however,this is not a necessary condition. In general,$T_{i} = {\sum\limits_{j = 1}^{m_{i}}t_{i,j}}$${and},\text{}{\tau = {\sum\limits_{i = 1}^{n}{\sum\limits_{j = 1}^{m_{i}}t_{i,j}}}}$

[0076] when all unit dose periods (t_(i,j)) within each of theprescribed dose periods (T_(i)) are equal, T_(i) = m_(i) * t_(i)${and},\text{}{\tau = {\sum\limits_{i = 1}^{n}{m_{i}*t_{i}}}}$

[0077] During each unit dose period (t_(i,j)), the valve 28 will beactuated through one complete cycle, such that it is in one position(i.e., designated open) for a fraction of the unit dose period (t_(i,j))and in a second position (i.e., designated closed) for the balance ofthe unit dose period (t_(i,j)). Those skilled in the art will readilyappreciate that it would also be possible to use one or more valves tomove between two or more position during any given unit dose period(t_(i,j)), and it would also be possible for such valve(s) to movebetween different positions during the same or different unit doseperiods (t_(i,j)).

[0078] In the simplified embodiment described herein, the controller 30determines a timing for keeping the valve 28 in an open state based onthe most recent estimate or measurement of the flow parameters(ΔP_(1,j)) and (R_(1,j)). The flow parameters are assumed (approximated)to be constant for at least the period of time that the valve 28 remainsin a given position. The following equations are useful in determiningthe amount of agent delivered (s_(i)) in a prescribed dose period(T_(i)), and the prescribed dosage pharmacologically perceived,$\begin{matrix}{t_{i,j} = \quad {t_{i,{j\quad {open}}} + t_{i,{j\quad {close}}}}} \\{s_{i} = \quad {C*{\sum\limits_{j = 1}^{m_{i}}( {{t_{i,{j\quad {open}}}*Q_{i,{j\quad {open}}}} + {t_{i,{j\quad {close}}}*Q_{i,{j\quad {close}}}}} )}}} \\{D_{i} = \quad {( {C \div T_{i}} )*{\sum\limits_{j = 1}^{m_{i}}( {{t_{i,{j\quad {open}}}*Q_{i,{j\quad {open}}}} + {t_{i,{j\quad {close}}}*Q_{i,{j\quad {close}}}}} )}}}\end{matrix}$

[0079] where,

[0080] t_(i,j open) is the duration of time that the valve 28 is in anopen state,

[0081] t_(i,j close) is the duration of time that the valve 28 is in aclosed state,

[0082] Q_(i,j open) is the flow rate when the valve 28 is in the openstate during unit dose period t_(i,j) and

[0083] Q_(i,j close) is the flow rate when the valve 28 is in the closedstate during unit dose period t_(i,j).

[0084] For passive pumping devices, the flow rate can be furtherdescribed by the following equations,

Q _(i,j open) =ΔP _(i,j open) ÷R _(i,j open)

Q _(i,j close) =ΔP _(i,j close) ÷R _(i,j close)

[0085] For restrictor-based passive pumping devices, ΔP_(i,j open) willoften be assumed to be equal to ΔP_(i,j close) for any given i,j. Thus,the position of the valve 28 simply changes the resistance magnitude (R)from R_(i,j open) to R_(i,j close). For passive pumping devicesincorporating a regulator, R_(i,j open) will often be approximated asequal to R_(i,j close) and the position of the valve 28 simply changesthe magnitude of ΔP from ΔP_(i,j open) to ΔP_(i,j close).

[0086] While in many cases Q_(i,j close) will be a zero value, i.e., thevalve 28 closes completely and flow stops, such is not a necessarycondition. For example, if maintaining the valve in an open state usesbattery power, then it may be advantageous to design the infusion deviceto have a non-zero Q_(i,j close) flow rate to thereby reduce the amountof time that the valve 28 needs be held open, and thereby conservebattery power. Alternatively, it may be possible to use a longer unitdose period (t_(i,j)) when using a non-zero Q_(i,j close) flow rate, andthereby reduce battery consumption by reducing the total number of unitdose periods. In cases when Q_(1,j close) is zero the equationsimplifies to,$s_{i} = {C*{\sum\limits_{j = 1}^{n}{t_{i,{j\quad {open}}}*Q_{i,{j\quad {open}}}}}}$

[0087] In a preferred embodiment, the unit dose period (t_(i,j)) ispre-determined, and t_(i,j open) is calculated to effect the desiredagent delivery. Those skilled in the art will readily recognize that itis possible to obtain the same effect by pre-determining t_(i,j open)and calculating t_(i,j closes) and thereby calculating t_(i,j) so thateffectively t_(i,j open) is held constant while t_(i,j) is varied.

[0088] The duration of the unit dose periods (t_(i,j)) is so chosen sothat they are: (i) short enough that the flow parameters (ΔP) and (R)are unlikely to change significantly so that the flow rates Q_(i,j open)and Q_(i,j close) can be approximated as being constant over the unitdose period (t_(i,j)); (ii) short enough that the open/close flow ratechanges are pharmacologically imperceptible or insignificant; and (iii)long enough to achieve acceptable levels of battery consumption (byminimizing the number of battery-consuming opening and closing cyclesfor the valve 28).

[0089] The above algorithms are maintained in non-volatile memory 32,and RAM 34 is used as a work space for at least the purposes of theabove calculations. The controller 30 is further coupled to aninternalized power source 36.

[0090] Reference is hereby made to FIG. 3, which illustrates but oneexample of the control signals delivered from the controller 30 to thevalve 28. The illustrated signals extend over a period of time in whichthe potential output flow rate decreases. For the exemplary illustratedunit dose periods (t_(i,j)), the duration of t_(1,x open) is increasedrelative to the duration of, for example, t_(1,1 open) for the “initial”dose periods (t_(i,j)). Notwithstanding, the duration of the unit doseperiod (t_(1,m,)=t₁ for all of m) is held constant. Of course, the notedchange in t_(i,j open) compensates for the change in infusate flow ratewithout express regard for the reason for such change in flow rate.

[0091] In some devices the pressure generated by the drive source 16will vary according to the volume of infusate remaining in the infusatereservoir 12. For example, in many devices the reservoir pressure dropsas the reservoir volume is nearly depleted and rises as the reservoirvolume nears (or exceeds) its rated capacity. In conventional infusiondevices this is a liability because it affects and therefore reduces theflow rate accuracy and the usable volume of the infusate reservoir 12.However, in the present invention this information can be an asset thatis used: (i) in the case of filled reservoirs, to alert a user so as toprevent a dangerous or undesirable overfilling of the pump; and/or (ii)in the case of nearly depleted reservoirs, to measure the volume offluid remaining in the infusate reservoir 12 by measuring the reservoirpressure, and if appropriate, alert a user that the device should berefilled. As described earlier, the controller can use this informationto adjust the open/close cycles, and thereby extend the usable volume ofthe infusion device without changing the physical size of the device.

[0092] In some clinical applications, the duration of the flow period(τ) can be limited by the compatibility or stability of an active agentin the infusate. “Compatibility” and “stability” are terms that areintended to capture all of the changes that can occur in the chemical,physical, pharmacological, or therapeutic properties of an infusate asit resides inside the infusate reservoir 12 of the drug delivery device.While not exhaustive, these changes include: (i) a decrease in thepotency of the active ingredient; (ii) an increase in the potency of theactive ingredient; and (iii) a change in infusate viscosity. Forexample, the potency of morphine sulfate in conventional implantableinfusion pumps is known to decrease by about 20% over a 90 day period,thus the lack of morphine stability restricts the maximum flow periodfor this agent to less than about 90 days (without regard to a potentialvolumetric capacity of the delivering infusion device). This fact, aswell as the fact that some conventional constant flow implantableinfusion pumps flow faster when full then they do when nearly empty,means that the actual drug dose received by the patient can varydramatically over a flow period (τ).

[0093] However, in the present invention look up tables or algorithmscan be used to compensate for known changes in the properties of theinfusate to adjust the flow controller over the course of the flowperiod (τ). This has at least two beneficial effects: (i) a more uniformamount of active agent is administered throughout the flow period (τ),thereby improving therapy and/or reducing side effects; and (ii) themaximum duration of the flow period (τ) can be extended so that more ofthe infusate reservoir can be used.

[0094] For any internally powered, implantable device, the life span ofits power source dictates its functional life. Of course, removal andreplacement of such device can be traumatic, as the patient is requiredto undergo a surgical procedure to effect such removal and replacement.As the benefits of any such implantable device are carefully weighedagainst the costs of use/replacement (e.g., hardware expense, physiciantime, hospitalization, etc.) as well as patient morbidity/mortality, itis imperative that efforts be made to provide an implantable devicecapable of sustaining sufficient operational life but remain cost andsize effective. Even when the device incorporates a rechargeable powersource (e.g., battery, capacity, etc.) minimizing power consumption isdesirable.

[0095] System power consumption is largely dictated by the powerconsumed to actuate the valve 28 through each open-close cycle for eachunit dose (d_(i,j)) and generally, to a lesser extent, by that requiredto make the measurements and calculations required to control the valvetiming. It is an objective of the present invention to safely minimizeand control a total current drain associated with the operation of thevalve 28. This control increases the predictability of a life-span of apower source (36, FIGS. 2A, 2B, and 2C). A generalized equation forcurrent drain resulting from valve actuation for one unit dose cycle(t_(i,j)) is:

I _(total) =I _(open) +I _(held open) ·t _(i,j open) +I _(close) +I_(held close) ·t _(i,j close)

[0096] where,

[0097] for a bi-stable valve, I_(held open) and I_(held close) are zerovalues, thus I_(total)=I_(open)+I_(close); and by comparison,

[0098] for a mono-stable valve, I_(close) and I_(held close) are likelyzero values, thus I_(total)=I_(open)+I_(held open)·t_(i,j open).

[0099] From the above examples, it can be readily seen that systemcurrent drain can be easily approximated from the operative nature of aselected valve, wherein the basis for valve selection depends upon anintended application.

[0100] Shortening the duration of the unit dose period (t_(i,j))improves flow accuracy, but at the expense of additional batteryconsumption to effect incremental valve actuation, computations, andpressure and/or temperature measurements. It will also be readilyapparent that for reasons of battery conservation, there may be timesand conditions within a given flow period (τ) when the prescribed doseperiod (T_(i)) and/or unit dose period (t_(i,j)) should be lengthened orshortened, and that based on the design of the device it may be possibleto predetermine these times (such as when the infusate reservoir isnearly empty), or to determine them in real time based on the input froma sensor. For example, when the reservoir is nearly depleted, ΔP maychange quickly meaning that the unit dose period (t_(i,j)) should beshortened to improve flow accuracy. Doing so, also effectively increasesthe amount of fluid from the infusate reservoir 12 that can be deliveredwithin flow accuracy specifications (i.e., the usable volume), which isa very desirable feature.

[0101] Based on a flow rate determined by the controller 30, anaccurate, dynamic calculation of remaining power source life can bemade. Likewise, an estimated life for the power source 36 can beapproximated from anticipated changes of the infusion device, or thepresent invention can be configured to pass calculated, real-timeinformation outside the patient to an external controller 50. For thisconcept, reference is made to FIG. 4, which illustrates a secondembodiment of the present invention.

[0102] Controller 50 communicates with the controller 30 through apatient's skin. Such communication is made, for example, using commonradio-frequency technology that is well known in the art. The manner andform of communication is not critical. Any means (e.g., IR, directconnection, etc.) that is capable of establishing a data transfer link,provided that the controller 50 and the implantable infusion device areprovided with the proper link components, is consistent with this aspectof the disclosed invention.

[0103] The controller 50 can provide information (e.g., softwareupdates, modification of calculation variables, for example, the unitdose period (t_(i,j)), t_(i,j open), etc.) to the controller 30 formaintaining accurate functionality of the infusion device. Moreover, thecontroller 50 can provide instructions to the controller 30 to changeany of these variables in response to changes in other parameters, e.g.,complex continuous infusion. The controller 50 could also transmit powerto the power source 36, if the power source 36 was of a rechargeablenature. Further yet, the controller 50 could transmit power directly tothe controller 30 via a carrier signal, e.g., using a radio-frequencycarrier signal.

[0104] It is contemplated that through the communication link betweenthe controller 30 and the controller 50, data can be uploaded from thecontroller 30 to the controller 50. To this end, the controller 50preferably includes a display 50 a, which can communicate information,e.g., life expectancy of the power source 28, to a user for real-timeconsideration. Additionally, diagnostic information regarding theoperability of the implantable infusion device can be supplied to theuser with only slight modification to the system illustrated in FIG. 2A.

[0105] In further reference to FIG. 4, an infusion device in accordancewith the present invention could be provided with a third pressuresensing device 40, which is positioned downstream of the valve 28.Further yet, additional variations of the specific arrangement of thecomponents of this system are illustrated in FIGS. 5-11.

[0106] From the initial pressure sensing devices 24 and 26 (and theoptional third pressure sensing device 40), the following informationcan be gathered and supplied back to a monitoring user via a data linkbetween the controller 30 and the controller 50:

Valve open, if P _(R) >P _(D1) ≅P _(D2);

Valve closed, if P _(R) ≅P _(D1) >P _(D2);

Catheter obstruction (e.g., kink, thrombosis), if

P _(R) ≅P _(D1) ≅P _(D2)

[0107] Further yet, transient responses from the second pressure sensingdevice 26 and the third pressure sensing device 40 during or proximateto an opening or closing of the valve 28 can be monitored to provideinformation regarding a system status. For example, in reference to theexemplary embodiment illustrated in FIG. 4, if prior to opening thevalve 28, P_(R)≅P_(D1)≧P_(D2), then as the valve 28 is opened, ameasured pressure transient enables a calculated appreciation of howfreely infusate is able to flow through the catheter 22 and the flowrestrictor 20. The rate of change of pressures P_(D1) and P_(D2) willcommunicate whether or not certain parts of the flow path are obstructed(e.g., completely or in part), and if obstructed, the location of suchobstruction relative to the flow path. Moreover, as the valve 28 isclosed, a measured pressure transient (between P_(D1) and P_(D2)) willallow an inference as to how freely infusate is able flow from theinfusate reservoir 12 through at least the restrictor 20. A rate ofchange of pressure will communicate whether the system filter(positioned between the infusate reservoir 12 and the restrictor 20) orthe restrictor 20 is partially or completely obstructed as might occurover the lifetime of the device. Of course, this information could bedisplayed on the display 50 a. In a like manner, as the valve 28 isclosed, a pressure transient measured for P_(D2) will allow an inferenceas to how freely infusate is able to flow through the delivery catheter22.

[0108] Provided that the critical portion of the flow path (i.e., thatportion through which regardless of any/all valve states all infusatemust flow) within the infusion device 10 is not completely occluded, thedata gained from the aforementioned detected conditions can enable amodification of controller variables (e.g., the unit dose period(t_(i,j)), t_(i,j open), etc.) so as to enable a targeteddosage/delivery rate to be maintained. The information gained can alsoprovide the managing clinician with valuable information to helpdetermine whether or not surgical intervention or a change in dosage isrequired.

[0109] As should also be noted, while the controller 50 has beendescribed as a device capable of establishing a data transfer link, itshould be further noted that modification of at least calculationvariables (e.g., the unit dose period (t_(i,j)), t_(i,j open), etc.) canbe accomplished through other non-invasive methods (e.g., magneticswitch control) or invasive methods (e.g., trocar).

[0110] While the invention has been described herein relative to anumber of particularized embodiments, it is understood thatmodifications of, and alternatives to, these embodiments, in particular,variants in the number, type, and configuration of the flowrestrictor(s), valve(s), and sensor(s), such modifications andalternatives realizing the advantages and benefits of this invention,will be apparent those of ordinary skill in the art having reference tothis specification and its drawings. It is contemplated that suchmodifications and alternatives are within the scope of this invention assubsequently claimed herein, and it is intended that the scope of thisinvention claimed herein be limited only by the broadest interpretationof the appended claims to which the inventors are legally entitled.

What is claimed is:
 1. An infusion device for implantation in a livingbody, the device comprising: at least one variable-volume chamber toreceive and transiently store a fluid infusate; at least one inletconduit, wherein each variable-volume chamber is in fluid communicationwith an inlet conduit; an energy source to effect an expulsion of storedinfusate from the at least one variable-volume chamber; at least oneoutlet conduit, in fluid communication with the chamber(s), tofacilitate the passage of infusate from the chamber(s) to a deliverysite; a flow resistor network including at least one flow restrictorpositioned relative to the outlet conduit; at least one pressure sensingdevice to measure a pressure differential across at least a portion ofthe flow restrictor network; at least one valve, positioned relative tothe outlet conduit, to selectively control an infusate output from thedevice; and a controller, coupled to the at least one pressure sensingdevice and to the at least one valve, to control an operation of the atleast one valve based on measured values obtained by the at least onepressure sensing device.
 2. A device in accordance with claim 1, whereina first pressure sensing device, which is one of the at least onepressure sensing device, is adapted to measure an infusate pressureacross the at least one valve.
 3. A device in accordance with claim 1,wherein a first pressure sensing device is adapted to measure aninfusate pressure prior to the at least one flow restrictor, and asecond pressure sensing device is adapted to measure an infusatepressure subsequent to the at least one flow restrictor, and wherein thefirst pressure sensing device and the second pressure sensing device aretwo of the at least one pressure sensing device.
 4. A device inaccordance with claim 1, further comprising a temperature sensor tomeasure an infusate temperature, and the controller is further coupledto the temperature sensor.
 5. A device in accordance with claim 4,wherein the controller is adapted to control the at least one valvebased also on measured values obtained by the temperature sensor.
 6. Aninfusion device for implantation in a living body having a collapsibleinfusate chamber, an energy source to collapse the chamber, and anoutlet flow path extending between the chamber and a device outlethaving a flow resistance, the device comprising: a pressure sensingmechanism to measure an infusate pressure differential across at least aportion of the flow resistance; a valve, which defines at least in partthe flow resistance, to selectively obstruct the outlet flow path; and acontroller, coupled to the pressure sensing mechanism and the valve, tocontrol an operation of the valve based on measured values obtained bythe pressure sensing mechanism, wherein a prescribed dose to bedelivered by the device consists of a plurality of unit dose cycles,each unit dose cycle being defined by an open-close cycle of the valve,and wherein the controller is adapted to regulate an operational timingof the open-close cycle of the valve to deliver a constant unit doseamount for each dose cycle.
 7. A device in accordance with claim 6,further comprising a flow resistor, which defines at least in part theflow resistance, positioned relative to the outlet conduit.
 8. A devicein accordance with claim 7, wherein the pressure sensing mechanismincludes a first pressure sensing device to measure an infusate pressureupstream of the flow restrictor and a second pressure sensing device tomeasure an infusate pressure downstream of the flow restrictor.
 9. Adevice in accordance with claim 6, wherein the pressure sensingmechanism is further adapted to measure an infusate pressure across thevalve.
 10. A device in accordance with claim 6, further comprising atemperature sensor to measure an infusate temperature, and thecontroller is further coupled to the temperature sensor.
 11. A device inaccordance with claim 10, wherein the controller is adapted to controlthe valve based also on measured values obtained by the temperaturesensor.
 12. A device in accordance with claim 6, wherein the controllervaries a duty cycle of the open-close cycle of the valve within aprescribed cycle period.
 13. A device in accordance with claim 6,wherein the controller varies a period of the open-close cycle.
 14. Aninfusion device for implantation in a living body having a collapsibleinfusate chamber to transiently store an active agent-containinginfusate, an energy source to collapse the chamber, and an outlet flowpath extending between the chamber and a device outlet having a flowresistance, the device comprising: a pressure sensing mechanism tomeasure an infusate pressure differential across at least a portion ofthe flow resistance; a valve, which defines at least in part the flowresistance, to selectively obstruct the outlet flow path; and acontroller, coupled to the pressure sensing mechanism and the valve, tocontrol an operation of the valve based on measured values obtained bythe pressure sensing mechanism, wherein a prescribed dose, to bedelivered over a prescribed dose period, consists of a plurality of unitdose cycles, each unit dose cycle being defined by an open-close cycleof the valve, and wherein the controller is adapted to regulate anoperational timing of the open-close cycle of the valve to compensatefor changes in the active agent-containing infusate, thereby maintaininga prescribed dose of active agent over the prescribed dose period.
 15. Adevice in accordance with claim 14, wherein the operational timing thatis subject to regulation by the controller is a duty cycle of theopen-close cycle of the valve.
 16. An infusion device for implantationin a living body having a collapsible infusate chamber to transientlystore an active agent-containing infusate, an energy source to collapsethe chamber, and an outlet flow path extending between the chamber and adevice outlet having a flow resistance, the device comprising: atemperature sensing device to measure an infusate temperature; a valve,which defines at least in part the flow resistance, to selectivelyobstruct the outlet flow path; and a controller, coupled to thetemperature sensing device and the valve, to control an operation of thevalve based on measured values obtained by the temperature sensingdevice, wherein a prescribed dose, to be delivered over a prescribeddose period, consists of a plurality of unit dose cycles, each unit dosecycle being defined by an open-close cycle of the valve, and wherein thecontroller is adapted to regulate an operational timing of theopen-close cycle of the valve based on a change in infusate temperaturemeasured by the temperature sensing device.
 17. A device in accordancewith claim 16, wherein the operational timing that is subject toregulation by the controller is a duty cycle of the open-close cycle ofthe valve.
 18. An infusion device for implantation in a living bodyhaving a collapsible infusate chamber to transiently store an infusate,an energy source to collapse the chamber, and an outlet flow pathextending between the chamber and a device outlet having a flowresistance, the device comprising: a pressure sensing mechanism tomeasure an infusate pressure differential across at least a portion ofthe flow resistance; a valve, which defines at least in part the flowresistance, to selectively obstruct the outlet flow path; and acontroller, coupled to the pressure sensing mechanism and the valve, tocontrol an operation of the valve based on measured values obtained bythe pressure sensing mechanism, wherein a prescribed dose, to bedelivered over a prescribed dose period, consists of a plurality of unitdose cycles, each unit dose cycle being defined by an open-close cycleof the valve, and wherein the controller is adapted to regulate anoperational timing of the open-close cycle of the valve based on achange in flow resistance.
 19. A device in accordance with claim 18,wherein the operational timing that is subject to regulation by thecontroller is a duty cycle of the open-close cycle of the valve.
 20. Aninfusion device for implantation in a living body having a collapsibleinfusate chamber to transiently store an infusate, an energy source tocollapse the chamber, and an outlet flow path extending between thechamber and a device outlet having a flow resistance, the devicecomprising: a pressure sensing mechanism to measure an infusate pressuredifferential across at least a portion of the flow resistance; a valve,which defines at least in part the flow resistance, to selectivelyobstruct the outlet flow path; and a controller, coupled to the pressuresensing mechanism and the valve, to control an operation of the valvebased on measured values obtained by the pressure sensing mechanism,wherein a prescribed dose, to be delivered over a prescribed doseperiod, consists of a plurality of unit dose cycles, each unit dosecycle being defined by an open-close cycle of the valve, and wherein thecontroller is adapted to selectively regulate an operational timing ofthe open-close cycle of the valve in accordance with a volumethen-determined to be present within the infusate chamber.
 21. A devicein accordance with claim 20, wherein the operational timing that issubject to regulation by the controller is a duty cycle of theopen-close cycle of the valve.
 22. An infusion device for implantationin a living body having a collapsible infusate chamber, an energy sourceto collapse the chamber, and an outlet flow path, having a flowresistance, that extends between the chamber and a device outlet, thedevice comprising: a flow restrictor, positioned relative to the outletflow path, which defines in part the flow resistance; a valve, whichdefines in part the flow resistance, to selectively obstruct the outletflow path; a pressure sensing device to measure an infusate pressureacross at least a portion of the flow resistance; and a controller,coupled to the pressure sensing device and the valve, to control anoperation of the valve to selectively obstruct the outlet flow path,wherein the controller is adapted to assess whether the flow resistancehas undesirably changed based on measured values obtained from thepressure sensing device.
 23. A device in accordance with claim 22,wherein the pressure sensing mechanism includes a first pressure sensingdevice to measure an infusate pressure upstream of the valve and asecond pressure sensing device to measure an infusate pressuredownstream of the valve.
 24. A device in accordance with claim 22,wherein the pressure sensing mechanism is further adapted to measure aninfusate pressure across the flow restrictor, and the controller isadapted to control the valve based also on measured infusate pressurevalues across the flow restrictor.
 25. A device in accordance with claim22, wherein the controller is adapted to identify a change in the flowresistance upstream of the valve based on measured values obtained fromthe pressure sensing mechanism.
 26. A device in accordance with claim22, wherein the controller is adapted to identify a change in the flowresistance downstream of the valve based on measured values obtainedfrom the pressure sensing mechanism.
 27. A method of controllinginfusate output from an implantable infusion device for a prescribeddose period, the device having a collapsible infusate chamber, an energysource to collapse the chamber, and an outlet flow path extendingbetween the chamber and a device outlet, wherein the outlet flow pathincludes a restrictor and a valve to selectively and at least partiallyocclude the outlet flow path, comprising the steps of: dividing theprescribed dose period into a plurality of unit dose periods, whereineach unit dose period is defined by an open-close cycle of the valve;and modifying a duty cycle of the open-close cycle of the valve so as tomaintain a unit dose for each unit dose period.
 28. A method inaccordance with claim 27, wherein the open-close cycle is defined by afixed period.
 29. A method of controlling infusate output from animplantable infusion device for at least one prescribed dose period, thedevice having a collapsible infusate chamber, an energy source tocollapse the chamber, and an outlet flow path extending between thechamber and a device outlet, wherein the outlet flow path includes arestrictor and a valve to selectively and at least partially occlude theoutlet flow path, comprising the steps of: dividing the prescribed doseperiod into a plurality of unit dose periods, wherein each unit doseperiod is defined by an open-close cycle of the valve; measuring aninfusate pressure differential across the restrictor; and modifying anoperational timing of the open-close cycle of the valve, in accordancewith a measured infusate pressure differential, so as to maintain a unitdose for each unit dose period.
 30. A method in accordance with claim29, wherein a plurality of prescribed dose periods define a flow period,and further comprising the step of dividing the flow period into theplurality of prescribed dose periods.
 31. A method in accordance withclaim 29, wherein the operational timing that is subject to regulationby the controller is a duty cycle of the open-close cycle of the valve.32. A method in accordance with claim 29, further comprising the step ofmeasuring an infusate temperature, wherein the step of modifying iseffected also in accordance with a measured temperature.
 33. A method inaccordance with claim 29, further comprising the steps of: actuating thevalve so as to effect a change in an occluded state of the outlet flowpath; and measuring a transient pressure profile across the valve.
 34. Amethod in accordance with claim 33, wherein the infusion device isadapted to communicate with a controller external to the patient, andfurther comprising the step of transmitting a signal to the controller,wherein the signal corresponds to the measured pressure profile.
 35. Amethod in accordance with claim 33, further comprising the step ofassessing a rate of change of a measured pressure profile at or aboutsaid actuating step.
 36. A method in accordance with claim 29, whereinthe infusion device is adapted to communicate with a controller externalto the patient, and further comprising the step of transmitting a signalto the controller, wherein the signal is representative of the measuredinfusate pressure differential.
 37. A method of controlling infusateoutput from an implantable infusion device for at least one prescribeddose period, the device having a collapsible infusate chamber totransiently store an active agent-containing infusate, an energy sourceto collapse the chamber, and an outlet flow path extending between thechamber and a device outlet, wherein the outlet flow path includes arestrictor and a valve to selectively and at least partially occlude theoutlet flow path, comprising the steps of: dividing the prescribed doseperiod into a plurality of unit dose periods, wherein each unit doseperiod is defined by an open-close cycle of the valve; and modifying anoperational timing of the open-close cycle of the valve to compensatefor changes in the active agent-containing infusate, thereby maintaininga prescribed dose of active agent over the prescribed dose period.
 38. Amethod in accordance with claim 37, wherein a plurality of prescribeddose periods define a flow period, and further comprising the step ofdividing the flow period into the plurality of prescribed dose periods,and wherein the step of modifying effects a control over the valve tocompensate for changes in the active agent-containing infusate, therebymaintaining a prescribed dose of active agent over each prescribed doseperiod in the flow period.
 39. A method of controlling infusate outputfrom an implantable infusion device for a prescribed dose period, thedevice having a collapsible infusate chamber, an energy source tocollapse the chamber, and an outlet flow path extending between thechamber and a device outlet, wherein the outlet flow path includes arestrictor and a valve to selectively and at least partially occlude theoutlet flow path, comprising the steps of: actuating the valve so as toeffect a change in an occluded state of the outlet flow path; measuringa transient pressure profile across the valve; and assessing a rate ofchange of the pressure profile during the actuating step.
 40. A methodin accordance the claim 39, wherein the step of assessing can reveal anundesired flow restriction upstream of the valve based on a rate ofchange of a measured pressure profile.
 41. A method in accordance theclaim 39, wherein the step of assessing can reveal an undesired flowrestriction downstream of the valve based on a rate of change of ameasured pressure profile.
 42. A method in accordance the claim 39,wherein the step of assessing can reveal a valve malfunction.
 43. Amethod in accordance the claim 39, wherein the step of assessing canreveal changes in infusate delivery caused by changes in certainproperties of the infusate based on a rate of change of a measuredpressure profile, the certain properties being of the group of:physical, chemical, therapeutic, and pharmacological.
 44. A method inaccordance the claim 39, wherein the step of assessing can reveal acatheter malfunction.
 45. An infusion device for implantation in aliving body, the device comprising: a variable-volume chamber to receiveand transiently store a fluid infusate; an inlet conduit, which is influid communication with the variable-volume chamber; an energy sourceto effect an expulsion of stored infusate from the chamber; an outletconduit, in fluid communication with the chamber, to facilitate thepassage of infusate from the chamber to a delivery site; a flowrestrictor, positioned relative to the outlet conduit, to define amaximum infusate flow rate output from the device; a first pressuresensing device to measure an infusate pressure upstream of the flowrestrictor; a second pressure sensing device to measure an infusatepressure downstream of the flow restrictor; a valve to selectivelycontrol an infusate output from the device; and a controller, coupled tothe first pressure sensing device, the second pressure sensing device,and the valve, to control an operation of the valve based on measuredvalues obtained by the first and second pressure sensing devices.